Angiotensin II provokes podocyte injury in murine model of HIV-associated nephropathy
Angiotensin II provokes podocyte injury in murine model of HIV-associated nephropathy
复制标题
DOI：
10.1152/ajprenal.00162.2007
复制
发表时间：
2007-10-01
影响因子：
4.2
通讯作者：
Nojima, Yoshihisa
中科院分区：
文献类型：
--
作者：
Ideura, Hiroshi;Hiromura, Keiju;Nojima, Yoshihisa
使用 Podocin 启动子和四环素诱导系统在足细胞中选择性表达人类免疫缺陷病毒 (HIV)-1 辅助基因之一 vpr 的条件转基因小鼠会出现与 HIV 相关肾病 (HIVAN) 患者相似的肾损伤。我们已经证明，半肾切除术会加速足细胞损伤，而血管紧张素 II (ANG II) 1 型受体阻滞剂 (ARB) 可以减轻足细胞损伤。目前的研究进一步探讨了 ANG II 在该小鼠模型中 HIVAN 发生中的作用。通过ANG II输注，在开始施用多西环素以诱导足细胞中vpr表达后1周观察到大量蛋白尿。 2周时观察到足细胞的严重形态和表型变化，以及广泛的肾小球硬化。输注去甲肾上腺素代替 ANG II，可将全身血压升高至与使用 ANG II 相同的水平。然而，在注射去甲肾上腺素的小鼠中，白蛋白尿和肾小球损伤是轻微的。使用 ARB 奥美沙坦治疗几乎完全抑制肾小球损伤。相比之下，用血管扩张剂肼屈嗪降低血压可以部分减少蛋白尿，但不会产生任何组织学变化。单独输注 ANG II（不含多西环素）可导致较低水平的蛋白尿和最小的组织学变化。这些数据表明，在 HIVAN 小鼠模型中，过量的 ANG II 会加速 vpr 诱导的足细胞损伤。
Conditional transgenic mice that express one of the human immunodeficiency virus (HIV)-1 accessory genes, vpr, selectively in podocytes using a podocin promoter and a tetracycline-inducible system develop renal injuries similar to those of patients with HIV-associated nephropathy (HIVAN). We have shown that a heminephrectomy accelerates podocyte injury, which is alleviated by angiotensin II (ANG II) type 1 receptor blocker (ARB). The current study further explores the role of ANG II in the genesis of HIVAN in this murine model. With ANG II infusion, heavy proteinuria was observed at 1 wk after the initiation of doxycycline administration to induce vpr expression in podocytes. Severe morphological and phenotypical changes in the podocytes were observed at 2 wk, together with extensive glomerulosclerosis. Norepinephrine infusion, instead of ANG II, increased the systemic blood pressure to the same level as that achieved using ANG II. However, albuminuria and glomerular injury were modest in norepinephrine-infused mice. Treatment with an ARB, olmesartan, almost completely inhibited glomerular injury. In contrast, lowering the blood pressure with a vasodilator, hydralazine, partially decreased albuminuria but did not produce any histological changes. ANG II infusion alone without doxycycline resulted in a lower level of albuminuria and minimal histological changes. These data demonstrate that excessive ANG II accelerates vpr-induced podocyte injury in a mouse model of HIVAN.